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Letter Cite This: Org. Lett. 2018, 20, 493−496

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Role of Ring Ortho Substituents on the Configuration of Carotenoid Polyene Chains Minsoo Kim,† Hyunuk Jung,† Albert C. Aragonès,‡ Ismael Díez-Pérez,*,‡ Kwang-Hyun Ahn,§ Wook-Jin Chung,† Dahye Kim,† and Sangho Koo*,† †

Department of Energy Science and Technology and Department of Chemistry, Myongji University, Myongji-Ro 116, Cheoin-Gu, Yongin, Gyeonggi-Do 17058, Korea ‡ Department of Chemistry, Faculty of Natural & Mathematical Sciences, King’s College London, Britannia House, 7 Trinity Street, London SE1 1DB, United Kingdom § Department of Applied Chemistry, Kyung Hee University, Yongin, Gyeonggi-Do 17104, Korea S Supporting Information *

ABSTRACT: The 9-(Z)-configuration was exclusively obtained in the carotenoid polyene chain irrespective of olefination and disconnection methods for terminal ortho-unsubstituted benzene rings. The 2,6-dimethyl substituents in the terminal rings secure an all-(E)-polyene structure. The single molecular conductance of the pure 9-(Z)-carotene was measured for the first time to be 1.53 × 10−4 ± 6.37 × 10−5G0, whose value was 47% that of the all-(E)-carotene ((3.23 × 10−4) ± (1.23 × 10−4) G0).

C

Scheme 1. Disconnection Approaches to 9,9′,13,13′Tetramethylcarotene Wire 1

arotenoids are structurally characterized by the conjugated polyene chain, which endows the red pigments with lightharvesting and energy transferring abilities1 as well as strong antioxidant activity.2 Even though 256 stereoisomers are theoretically obtainable by the palindromic structure containing nine CC bonds, only a dozen stereoisomers were reported.3 All-(E)-carotenes are generally the most stable form and can be prepared by chemical synthesis.4 (Z)-Carotenes are also widespread in nature (e.g., bixin, phytofluene, prolycopene, etc.), 9-(Z)-isomers being prevalent.5 Since the geometry of carotenoids determines their physicochemical characteristics as well as their biological activities,6 it is desirable to develop a stereoselective synthetic method for each isomer. In our research directed to the utilization of carotenoids as molecular wires, a series of phenyl-substituted all-(E)-carotenoids was designed7 in which the phenyl groups not only stabilize the polyene chain8 but also impart diverse electron-conducting abilities to the chain.9 We were interested in the conductance behavior of carotene 1 containing the natural form of 9,9′,13,13′tetramethyl substituents (Scheme 1).10 Efforts to synthesize all(E)-carotene 1 were unsuccessful, and on the contrary, it was found that the 9-(Z)-isomer was obtained exclusively. Since there have been controversial reports on the molecular conductance behaviors of E/Z isomers of azobenzene and diphenylethylene,11,12 and since only the theoretical calculation for the conductance of (Z)-carotene was available,13 it was a good opportunity to experimentally investigate the conductance of the (Z)-isomer. It was still necessary to synthesize the corresponding all-(E)-carotene in order to complete the conductance study on the E/Z isomerism of carotenoids. We devised a method to construct all-(E)-9,9′,13,13′-tetramethyl carotene based on the fact that β-carotene and isorenieratene14 can be easily prepared in © 2018 American Chemical Society

all-(E) form, in which the ring o-methyl substituents were conceived to play an important role in controlling the configuration of the polyene chain. We herein report the syntheses and conductance measurements of 9-(Z)- and all-(E)9,9′,13,13′-tetramethylcarotenes. Typical disconnection approach to 9,9′,13,13′-tetramethylcarotene 1 was either using C10 dihalide 315 or C10 dialdehyde 416 (Scheme 1). The functional group X of the coupling partner 2 may be selected among benzenesulfonyl (−SO2Ph), benzothiazolesulfonyl (−SO2BT), and triphenylphosphonium bromide (−PPh3Br) according to the olefination methods of Julia,17 Julia−Kocienski,18 and Wittig,19 respectively (Scheme 1). The terminal methylthio group was designed as a linker to allow the carotene wire for reliable contact with gold electrodes for Received: December 18, 2017 Published: January 10, 2018 493

DOI: 10.1021/acs.orglett.7b03930 Org. Lett. 2018, 20, 493−496

Letter

Organic Letters conductance measurement.20 Other disconnection utilizing C20 crocetindial 5 and Wittig salt 6 was also tested. The synthesis began with the preparation of the key building blocks 2 with methylthio linker (Scheme 2). Dienyl sulfones 2a

complicated due to the formation of the regioisomer at the benzylic position. In situ generated triphenylphosphonium bromide from PPh3 and NBS successfully activated the tertiary carbinol by forming triphenylphosphonium oxide, which was replaced by PPh3 at the less hindered terminal vinyl carbon to provide the Wittig salt 2c quantitatively. Sulfone-mediated 2:1 coupling between dienyl sulfone 2a and C10 dihalide 3 was carried out with t-BuOK in DMF at −20 °C to produce C40 trisulfone 12 (92% yield, Figure 1). Olefinations

Scheme 2. Synthesis of the Key Building Blocks 2 Containing a Methylthio Linker

(X = −SO2Ph) and 2b (X = −SO2BT) were synthesized by the application of the two step protocol utilizing indium-mediated addition of chloroallylic sulfones 8a (R = Ph) and 8b (R = BT) to 4-(methylthio)benzaldehyde (9),21 followed by the oxonia-Cope rearrangement of the resulting homoallylic alcohols 10a and 10b, respectively.22 The C5 chloroallylic sulfones 8a and 8b were prepared from isoprene. Chlorohydrin formation (58% yield) by NCS in water/DMF followed by bromination (92% yield) with PBr3 and catalytic CuI accompanying allylic migration produced allylic dihalide 7 (E:Z = 6:1).23 Selective allylation at the more reactive carbon containing bromide by NaSO2Ph provided chloroallylic benzenesulfone 8a (60% yield)24 or by BT-SH using K2CO3 in acetone produced the corresponding BT-sulfide (95% yield). Sulfur oxidation by H2O2 with catalytic sodium tungstate (Na2WO4·2H2O) gave rise to chloroallylic benzothiazolesulfone 8b (51% yield).25 The E/Z alkene configurations were maintained as 6:1 through the allylation steps. Indium-mediated Barbier addition of C5 chloroallylic sulfone 8a (R = Ph) to 4-(methylthio)benzaldehyde (9) was carried out at 80 °C in a 4:1 H2O/THF to produce homoallylic alcohol 10a (64% yield) with 2:1 anti (OH vs SO2Ph) selectivity.22 The same condition was not effective for the allylindium formation from chloroallylic sulfone 8b (R = BT). Activation of the allylic chloride by Finkelstein reaction (NaI, acetone) was necessary to produce the corresponding homoallylic alcohol 10b (R = BT) in 45% yield with 2:1 antiselectivity. A new E/Z ratio was established in the allyl indium species according to the alkenyl substituents regardless of the original E/Z ratio of allyl halide 8.24 The oxonia-Cope rearrangement of homoallylic alcohol 10a (R = Ph) was performed using stoichiometric camphoresulfonic acid and aldehyde 9 at 80 °C to provide dienyl sulfone 2a in 77% yield (E/Z = 2:1 at C-2).22 Milder condition of catalytic Sn(OTf)2 and aldehyde 9 at 40 °C was utilized for the rearrangement of homoallylic alcohol 10b (R = BT) to give dienyl sulfone 2b in 61% yield (E/Z = 1.5:1 at C-2).24 All-Edienyl sulfone 2a and 2b can be easily obtained by recrystallization from MeOH or EtOH. The corresponding Wittig salt 2c (Y = H) was obtained from 4-(methylthio)benzaldehyde (9). Aldol condensation with acetone produced conjugated ketone 11 (87% yield), to which vinyl Grignard addition at −78 °C yielded the tertiary vinyl carbinol. The condition for bromination with allylic migration is crucial in the formation of Wittig salt 2c. Acidic conditions allowing carbocation intermediate such as PBr3 and HBr were

Figure 1. Products and intermediates obtained in the synthetic approaches to carotene wire 1.

were sequentially conducted first by the Ramberg−Bäcklund reaction (KOH, t-BuOH, CCl4) and then by base-promoted (KOMe) double dehydro-desulfonation to exclusively and unexpectedly produce 9-(Z)-carotene 13 (overall 14% yield after recrystallization) instead of all-(E)-carotene 1.26 The 9-(Z)configuration was assigned by the number of 1H and 13C peaks from the dissymmetrical structure and more specifically by NOE (7%) between H11 and H8 in NMR analysis (see the Supporting Information for COSEY, NOESY, and 1D NOE). The Julia−Kocienski olefination was then tried to minimize possible isomerization. Dienyl BT-sulfone 2b (2 equiv) was coupled with C10 dial 4 at −78 °C and warmed to 25 °C to produce monocoupled all-(E)-apocarotenal 14a (Y = H, 35% yield), which was reacted again with 2b to exclusively give 9-(Z)carotene 13 (37% yield). Olefination by the Wittig salt 2c (5 equiv) and C10 dial 4 (NaOMe at 80 °C) also produced all-(E)apocarotenal 14a (56% yield) as a major product, which was reacted with the Wittig salt 2c to give 9-(Z)-carotene 13 again (17% recrystallized yield). A different disconnection approach utilizing the Wittig reaction of benzyl triphenylphosphonium bromide 6 (5 equiv) and C20 crocetin dial 5 (NaOMe at 80 °C) provided again 9-(Z)-carotene 13 exclusively (13% yield after recrystallization). A series of questions arose: Is the 9-(Z)-isomer 13 more stable than all-(E)-carotene 1? How can β-carotene be easily obtained as all-(E)-form? Is it possible to synthesize all-(E)-9,9′,13,13′tetramethylcarotene by introducing o-methyl substituents into the benzene rings (e.g., compound 15 in Figure 1) just like the ring o-methyl substituents of β-carotene? In order to answer these questions, we decided to synthesize Wittig salt 2d (Y = Me, in Scheme 2). An efficient synthesis of 2,6-dimethyl-4(methylthio)benzaldehyde (16) was devised from the Hagemman’s ester 18, which was prepared (95% yield) by a one-pot reaction between ethyl acetoacetate (2 equiv) and acetaldehyde (Scheme 3).27 Lawesson’s reagent allowed the formation of thione 19, which was not easily purified. It was suspected to be consisted of a mixture of 19 and its dimeric form through a disulfide bond, because S-methylation (NaH, MeI) gave only 494

DOI: 10.1021/acs.orglett.7b03930 Org. Lett. 2018, 20, 493−496

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Organic Letters Scheme 3. Preparation of the Key Building Block 22 for All(E)-Carotene 15

40% yield of methyl sulfide 20; oxidation of the Lawesson’s reaction product by NBS and catalytic TMS·OTf produced disulfide 21 in 73% yield.28 Oxidative aromatization of 20 by NBS produced ethyl 2,6-dimethyl-4-(methylthio)benzoate (22) in 83% yield.28 The key building block 22 can be better prepared by Indium reduction29 of disulfide 21 to the monomeric thiol from, followed by S-methylation (NaH, MeI) in overall 80% yield. Wittig salt 2d was prepared as demonstrated for Wittig salt 2c in Scheme 2. Ethyl benzoate 22 was converted to the corresponding aldehyde 16 by LAH reduction (50% yield) and PDC oxidation (73% yield). Aldol condensation with acetone provided unsaturated ketone 17 (94% yield), which was reacted with vinylmagnesium bromide to produce tertiary vinylcarbinol. Allylic bromination and phosphorylation at the terminal vinyl carbon were routinely carried out by HBr (1 equiv) and PPh3 (1 equiv) to produce Wittig salt 2d quantitatively (Scheme 2). Wittig reaction of 2d (2.5 equiv) and C10 dialdehyde 4 (NaOMe in MeOH/toluene at reflux) eventually produced all-(E)9,9′,13,13′-tetramethylcarotene 15 (23% yield) and monocoupled all-(E)-apocarotenal 14b (67% yield), which was coupled again with Wittig salt 2d to give all-(E)-carotene 15 in 92% yield. The o-methyl ring substituents really play an important role in controlling the (E)-configuration of the polyene chain. The distinctive triplet UV absorptions for 9-(Z)-carotene 13 were observed at 462, 485 (maximum), and 517 nm in CH2Cl2. On the other hand, only the maximum peak at 472 nm was discernible with a shoulder around 500 nm for all-(E)-carotene 15 (see the SI). It is interesting to note that λmax for 9-(Z)carotene 13 is red-shifted by 13 nm compared to that of all-(E)carotene 15, which may be the reason for the exclusive formation of 9-(Z)-form by effective conjugation of the polyene chain. DFT calculation (structure optimization: m062x/6-311G(d,p); basis set for free energy: cc-pVTZ) supports this result that 9-(Z)carotene 13 is more stable than all-(E)-carotene 1 by 1.55 kcal/ mol, and that all-(E)-carotene 15 with 2,6-dimethyl groups is more stable than its 9-(Z)-isomer by 2.64 kcal/mol (see SI). The static version30 of the STM break junction method31 is a valuable tool to measure single molecule conductance for carotenoids without applying mechanical strains to the formed molecular junction. An electric circuit is stochastically formed and broken between a voltage-biased gold STM tip and supporting gold electrodes through a residing carotenoid molecule with methylthio-linkers in dilute mesitylene (0.5 μM) solution. The current is then monitored as a function of time. When a single carotenoid backbone transiently bridges the gap, a telegraphic signal is observed in the current transient (see Figure 2a,b). Tens of such current telegraphic traces are then accumulated in a single 2-dimensional map (blinking map, see

Figure 2. (a, b) Representative current transient for (a) 9-(Z)- and (b) all-(E)-9,9′,13,13′-tetramethylcarotenes, displaying blinking features as a result of transient single-carotene molecules being trapped in the tunneling junction. (c, d) 2-Dimensional blinking maps for (c) 9-(Z)and (d) all-(E)-9,9′,13,13′-tetramethylcarotenes, respectively, built out of more than 30 individual current traces. The left panel of each 2dimensional map shows vertically the 1-dimensional counts distribution. The maxima of the Gaussian fits (solid lines in the vertical 1-D histograms) projected over the Y-axis (G) provide the averaged conductance of the single-molecule junction. The applied bias voltage (V) was set to 7 mV.

Figure 2c,d) by setting all the current jumps to the same time origin and tunneling background subtraction. The averaged molecular conductance values (expressed versus the quantum of conductance, G0 = 77.4 μS) for both carotenoid molecules were statistically obtained by Gaussian fittings of the peaks in the 1dimensional histogram representation of the two blinking maps (see Figures 2c,d): ((1.53 × 10−4) ± (6.37 × 10−5))G0 and ((3.23 × 10−4) ± (1.23 × 10−4))G0 for 13 and 15, respectively. The experimental conductance value for 9-(Z)-carotene 13 was 47% of that of all-(E)-carotene 15, which agrees well with the theoretical (DFT) calculations of 55% reduction for the 7-(Z)isomer compared to the all-(E)-carotene.13 It was assumed that both carotenes make stable interactions with the gold STM tip through methylthio linkers. The blinking signals in Figure 2 arise from strong tip-molecule interactions. Forces have been measured in break-junction experiments and the breaking features have been ascribed to the formation of a covalent Au−S bond.32 The lower accessibility of the linker group might affect the yield of the single-molecule junction experiments, but the observed result shows that this is not the case. STM tips are known to present a number of asperities on their surface. They are far from being a smooth concave element, and such asperities can act as anchoring points to the methylthio group of 9-Z-isomer. Short switching molecules under UV/vis irradiation such as azobenzene and diphenylethylene were reported to exhibit high conducting profile for cis-isomer, which is mainly because of the difference in tunneling length of the molecule spanned between the electrodes.11 Controversially, cis-azobenzene was also reported to give lower conductance by breaking π-conjugation along the molecular frame.12 We experimentally demonstrated that the trans-isomer is more conductive for the polyene chain of carotenoids. DFT calculations of frontier molecular orbitals in both cases show good delocalization of orbitals, being the HOMO−1 and −2 energetically the closest orbitals to the Au electrode Fermi level (−5 eV). The slight closer proximity in energy in all-(E) case (up to 70 mV in HOMO−2 case) might 495

DOI: 10.1021/acs.orglett.7b03930 Org. Lett. 2018, 20, 493−496

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Organic Letters

(8) (a) Wrona, M.; Rozanowska, M.; Sarna, T. Free Radical Biol. Med. 2004, 36, 1094−1101. (b) Fuciman, M.; Chabera, P.; Zupcanova, A.; Hribek, P.; Arellano, J. B.; Vacha, F.; Psencik, J.; Polivka, T. Phys. Chem. Chem. Phys. 2010, 12, 3112−3120. (9) (a) Zhao, Y.; Lindsay, S.; Jeon, S.; Kim, H.-J.; Su, L.; Lim, B.; Koo, S. Chem. - Eur. J. 2013, 19, 10832−10835. (b) Aragones, A. C.; Darwish, N.; Im, J.; Lim, B.; Choi, J.; Koo, S.; Diez-Perez, I. Chem. - Eur. J. 2015, 21, 7716−7720. (10) Ramachandran, G. K.; Tomfohr, J. K.; Li, J.; Sankey, O. F.; Zarate, X.; Primak, A.; Terazono, Y.; Moore, T. A.; Moore, A. L.; Gust, D.; Nagahara, L. A.; Lindsay, S. M. J. Phys. Chem. B 2003, 107, 6162−6169. (11) (a) Mativetsky, J. M.; Pace, G.; Elbing, M.; Rampi, M. A.; Mayor, M.; Samori, P. J. Am. Chem. Soc. 2008, 130, 9192−9193. (b) Martin, S.; Haiss, W.; Higgins, S. J.; Nichols, R. J. Nano Lett. 2010, 10, 2019−2023. (12) (a) Kumar, A. S.; Ye, T.; Takami, T.; Yu, B.-C.; Flatt, A. K.; Tour, J. M.; Weiss, P. S. Nano Lett. 2008, 8, 1644−1648. (b) del Valle, M.; Gutiérrez, R.; Tejedor, C.; Cuniberti, G. Nat. Nanotechnol. 2007, 2, 176−179. (13) Li, J.; Tomfohr, J. K.; Sankey, O. F. Phys. E 2003, 19, 133−138. (14) (a) Yamaguchi, M. Bull. Chem. Soc. Jpn. 1959, 32, 1171−1173. (b) Khosla, M. C.; Karrer, P. Helv. Chim. Acta 1960, 43, 453−457. (15) Ji, M.; Choi, H.; Jeong, Y. C.; Jin, J.; Baik, W.; Lee, S.; Kim, J. S.; Park, M.; Koo, S. Helv. Chim. Acta 2003, 86, 2620−2628. (16) (a) Babler, J. H. U. S. Patent 5 107 030, 1992. (b) Koo, S.; Choi, H.; Park, M.; Ji, M. U. S. Patent 6 403 838, 2002. (17) (a) Julia, M.; Arnould, D. Bull. Soc. Chim. Fr. 1973, 743−746. (b) Julia, M.; Arnould, D. Bull. Soc. Chim. Fr. 1973, 746−750. (18) (a) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Tetrahedron Lett. 1991, 32, 1175−1178. (b) Kocienski, P. J.; Bell, A.; Blakemore, P. R. Synlett 2000, 31, 365−366. (19) (a) Pommer, H. Angew. Chem. 1960, 72, 911−915. (b) Pommer, H. Angew. Chem. 1977, 89, 437−443. (20) Davis, J. J.; Coleman, K. S.; Busuttil, K. L.; Bagshaw, C. B. J. Am. Chem. Soc. 2005, 127, 13082−13083. (21) Min, J.-H.; Jung, S.-Y.; Wu, B.; Oh, J. T.; Lah, M.; Koo, S. Org. Lett. 2006, 8, 1459−1462. (22) Jung, S.-Y.; Min, J.-H.; Oh, J. T.; Koo, S. J. Org. Chem. 2006, 71, 4823−4828. (23) Lee, J. S.; Jeong, Y. C.; Ji, M.; Baik, W.; Lee, S.; Koo, S. Synlett 2004, 2004, 1937−1940. (24) Lim, B.; Oh, E.-T.; Im, J. O.; Lee, K. S.; Jung, H.; Kim, M.; Kim, D.; Oh, J. T.; Bae, S.-H.; Chung, W.-J.; Ahn, K.-H.; Koo, S. Eur. J. Org. Chem. 2017, 2017, 6390−6400. (25) Giam, C. S.; Kikukawa, K.; Trujillo, D. A. Org. Prep. Proced. Int. 1981, 13, 137−140. (26) Choi, H.; Ji, M.; Park, M.; Yun, I.-K.; Oh, S.-S.; Baik, W.; Koo, S. J. Org. Chem. 1999, 64, 8051−8053. (27) Chong, B.-D.; Ji, Y.-I.; Oh, S.-S.; Yang, J.-D.; Baik, W.; Koo, S. J. Org. Chem. 1997, 62, 9323−9325. (28) Kang, S.; Kim, D.; In, I. J.; Koo, S. Tetrahedron Lett. 2017, 58, 2264−2266. (29) Reddy, G. V. S.; Rao, G. V.; Iyengar, D. S. Synth. Commun. 2000, 30, 859−862. (30) Aragonès, A. C.; Haworth, N. L.; Darwish, N.; Ciampi, S.; Bloomfield, N. J.; Wallace, G. G.; Diez-Perez, I.; Coote, M. L. Nature 2016, 531, 88−91. (31) Xu, B.; Tao, N. J. Science 2003, 301, 1221−1223. (32) Frei, M.; Aradhya, S. V.; Hybertsen, M. S.; Venkataraman, L. J. Am. Chem. Soc. 2012, 134, 4003−4008.

account for the observed factor of 2 difference in the conductance, given their exponential dependence nature (see Tables S1-1 and S1-2). In conclusion, we were able to devise stereoselective synthetic methods for each of 9-(Z)- and all-(E)-carotene with the natural 9,9′,13,13′-tetramethyl substitution. Effective conjugation for 9(Z)-carotene 13 and repulsive steric interaction at the ring orthosubstituents for all-(E)-carotene 15 seem to be the major controlling factors for the configurations. Molecular conductance measurements using the static STM break junction method revealed all-(E)-carotene 15 is almost twice more conducting than 9-(Z)-carotene 13.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03930. Experimental procedure, analytical data, and DFT calculations for 9-(Z)-carotene 13 and all-(E)-carotene 15 (PDF) Analytical data and 1H 13C NMR spectra for all new compounds (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Sangho Koo: 0000-0003-4725-1117 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This research was supported by the Basic Science Research Program (NRF-2016R1A2B4007684) and by the Priority Research Centers Program (NRF-2009-0093816), both through the National Research Foundation of Korea, and also by the MINECO Spanish national project CTQ2015-64579-C3-3-P (MINECO/FEDER, EU) and start-up King’s College London financial support.

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REFERENCES

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DOI: 10.1021/acs.orglett.7b03930 Org. Lett. 2018, 20, 493−496